Bronchial hyperreactivity is a prominent feature of asthma. Indirect but compelling evidence suggests the possible involvement of increased pulmonary C-fiber excitability in the manifestation of bronchial hyperreactivity induced by airway mucosal injury. The objectives of this proposal are the following: 1) to characterize the stimulatory effect of hydrogen ions on pulmonary C-fibers, 2) to elucidate the mechanisms underlying this effect, and 3) to explore its potential role in the development of bronchial hyperreactivity. Proposed experiments are focused on two sources of H+ ions that are produced by tissue metabolism: lactic acid and CO2. An elevated level of lactic acid occurs commonly during severe exercise, tissue ischemia, and various pathologic conditions, but whether pulmonary C-fibers can be activated by excessive production of lactic acid is not known. The following three hypotheses will be tested: 1) pulmonary C-fibers can be activated by an increase in H+ concentration in pulmonary interstitial fluid (PIF), and lactic acid is particularly effective in stimulating these endings; 2) a substantial increase of CO2 tension in the alveolar gas can also exert a stimulatory effect on these afferents, and this action is brought about by an increase in the H+ concentration in the PIF; and 3) the stimulatory effect of H+ ions on these afferents can be potentiated by airway mucosal inflammation, in which the production and release of both cyclooxygenase metabolites and tachykinins are involved. In the proposed studies, mucosal inflammation will be induced by acute exposure of the lung to ozone or by hyperventilation with cold dry air. Pulmonary C-fiber afferent activity will be recorded in anesthetized rats by using a single-fiber recording technique, whereas pH in pulmonary venous blood will be measured continuously for estimation of the changes of pH in PIF during various experimental conditions. The relationship between changes in fiber activity and pulmonary venous pH will be established, and from this the threshold pH for stimulation can be determined. The feasibility and potential significance of the proposed studies have already been demonstrated in the preliminary experiments. These results will provide a more in-depth understanding of the chemosensitive properties of pulmonary C-fibers and their role in regulating the airway functions in various pathophysiological conditions.